Darunavir is a nonpeptidic protease inhibitor approved for use in the treatment of human immunodeficiency virus type 1 (HIV-1) infection and has the following chemical structure:
WO-2005/063770 discloses in Examples 7 a process for preparing darunavir by reacting carbonic acid 2,5-dioxo-1-pyrrolidinyl [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [referenced throughout this text as compound (A)], that was first prepared in situ, with 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide [referenced throughout this text as compound (B)] in ethyl acetate as solvent to which triethylamine was added as a base. The reaction was quenched by addition of methylamine in an aqueous solution in ethanol. The crude darunavir isolated from the reaction mixture was converted into its ethanolate form by crystallization from absolute ethanol with a yield of 71%.
WO-2005/063770 discloses in Examples 9 a process for preparing darunavir by reacting compound (A), that was first prepared in situ, with compound (B) in acetonitril as solvent to which triethylamine was added as a base. The reaction was quenched by addition of methylamine in an aqueous solution in ethanol. The crude darunavir isolated from the reaction mixture was converted into its ethanolate form by crystallization from absolute ethanol with a yield of 81%.
Journal of Medicinal Chemistry, vol. 48, p. 1813-1822 (2005) discloses the synthesis of darunavir as compound (la) by reacting compound (A) with compound (B) in dichloromethane as solvent in the presence of triethylamine as a base with a yield of 90%.

WO-2009/055006 discloses a process for preparing a deuterated form of darunavir by reacting carbonic acid 2,5-dioxo-1-pyrrolidinyl [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester with a deuterated form of 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide in dichloromethane as solvent in the presence of triethylamine as a base.
WO-2014/016660 discloses in Example 3 a process for preparing darunavir in its propionate solvate form by reacting carbonic acid 2,5-dioxo-1-pyrrolidinyl [(3R,3 aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester with 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide in a two phase mixture of ethyl acetate and water, followed by salt conversion with propionic acid with an overall yield of 90%.
It now has been found that darunavir can be obtained in a simplified procedure by reacting carbonic acid 2,5-dioxo-1-pyrrolidinyl [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester, i.e. compound (A), with 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-benzenesulfonamide, i.e. compound (B), in the absence of an organic base and ethanol as solvent while heating. Upon completion of the reaction, the reaction mixture is heated till homogeneous and then allowed to cool to ambient temperature whereby darunavir crystallizes in its monoethanolate form.
